研究中心本年度執行情形
本中心目前主要研究方向及這些計劃與國外各醫學研究中心合作之情形，以下列出各別研究方向參與的principal inverstigators ( PI )，以及研究成果：

1. 兒童感染症之臨床及流行病學研究
   1. 邱政洵醫師、蘇玲慧老師：進行沙門氏菌感染之臨床及流行病學研究。
   2. 黃玉成醫師：人類A型肝炎病毒、麻疹病毒在兒童流行病學上之血清型分析
   3. 陳志榮醫師、黃玉成醫師：MRSA感染之臨床及分子流行病學
   4. 謝育嘉醫師：肺炎鏈球菌感染之流行病學、抗藥性演化及致病性之相關研究
   5. 陳世彥醫師、黃冠穎醫師、黃玉成醫師、謝育嘉醫師、陳志榮醫師、邱政洵醫師、蔡七女老師、李忠城博士：流感病毒、輪狀病毒、諾羅病毒、腺病毒在兒童腸胃道感染症、肺炎、及中樞神經系統功能障礙之臨床及分子流行病學研究。
   6. 蔡明翰醫師、吳竹蘭部長及黃玉成醫師：社區型之肺結核桿菌與病毒共同感染對兒童健康的衝擊
   7. 蔡明翰醫師：社區型之ESBL抗藥大腸桿菌和綠膿桿菌造成感染的流行病分析
   8. 林建志醫師：感染相關發熱性癲癇及格林巴黎綜合症
   9. 吳竹蘭部長：廣泛抗藥性綠膿桿菌和困難腸梭菌的流行病分子分析
   10. 王盈翔醫師、徐任甫醫師、李建忠： B型鏈球菌(GBS)造成新生兒嚴重感染之相關研究
   11. 黃禹堯醫師、黃瓊慧醫師、陳怡文醫師: 糖尿病相關研究
       • Wang YH, Chen CL, Hou JN, Wang YR, Lin TY, Wang MH, Yang TH, Chu C, Chiu CH. Serotype distribution and resistance genes associated with macrolide and fluoroquinolone resistance in Streptococcus agalactiae isolates from a hospital in Southern Taiwan. Biomed J. 2015; 38(3):215-220.
       • Huang KY, Lin JJ, Chiu CH, Yang S, Tsao KC, Huang YC, Lin TY. A Potent Virus-Specific Antibody-Secreting Cell Response to Acute Enterovirus 71 Infection in Children. J Infect Dis. 2015 Sep 1;212(5):808-17.
       • Tang WF, Huang RT, Chien KY, Huang JY, Lau KS, Jheng JR, Chiu CH, Wu TY, Chen CY, Horng JT. Host MicroRNA miR-197 Plays a Negative Regulatory Role in the Enterovirus 71 Infectious Cycle by Targeting the RAN Protein. Journal of Virology. 2015; 90(3): 2016 90:3 1424-1438.
       • Lee CC,  Feng Y, Chen SY, Tsai CN, Lai MW, Chiu CH. Emerging Norovirus GII.17 in Taiwan. Clin Infect Dis. 2015 Dec 1;61(11):1762-4.
       • Chen SY, Feng Y, Chao HC, Lai MW, Huang WL, Lin CY, Tsai CN, Chen CL, Chiu CH. Emergence in Taiwan of novel norovirus GII.4 variants causing acute gastroenteritis and intestinal hemorrhage in children. J Med Microbiol 2015; 64(Pt5):544-50.
       • Huang KY, Lin JJ, Chiu CH, Yang S, Tsao KC, Huang YC, Lin TY. A potent virus-specific antibody-secreting cell response to acute enterovirus 71 infection in children. J Infect Dis. 2015 212(5): 808-817.
       • Lin TJ, Lin CF, Chiu CH, Lee MC, Horng JT. Inhibition of endosomal fusion activity of influenza virus by Rheum tanguticum (da-huang). Scientific Reports. 2016 Jun 15;6:27768.
       • Ho JY, Chern JH, Hsieh CF, Liu ST, Liu CJ, Wang YS, Kuo TW, Hsu SJ, Yeh TK, Shih SR, Hsieh PW, Chiu CH, Horng JT. In vitro and in vivo studies of a potent capsid-binding inhibitor of enterovirus 71. Journal of Antimicrobial Chemotherapy. 2016; 71(7): 1922-1932.
       • Cheng CH, Huang YC. Risk Factors and Management of Urinary Tract Infections in Children Aged 3 Months to 2 Years. Pediatr Neonatol. 2016 Jun 11. pii: S1875-9572(16)30073-0. doi: 10.1016/j.pedneo.2015.05.004. [Epub ahead of print]
       • Lai MY, Tsai MH, Lee CW, Chiang MC, Lien R, Fu RH, Huang HR, Chu SM, Hsu JF. Characteristics of neonates with culture-proven bloodstream infection who have low levels of C-reactive protein (≦10 mg/L). BMC Infect Dis. 2015 Aug 11;15:320.
       • Hsu JF, Chu SM, Lee CW, Yang PH, Lien R, Chiang MC, Fu RH, Huang HR, Tsai MH. Incidence, clinical characteristics and attributable mortality of persistent bloodstream infection in the neonatal intensive care unit. PLoS One. 2015 Apr 15;10(4):e0124567.
       • Hsu JF, Chu SM, Huang YC, Lien R, Huang HR, Lee CW, Chiang MC, Fu RH, Tsai MH. Predictors of clinical and microbiological treatment failure in neonatal bloodstream infections. Clin Microbiol Infect. 2015 May;21(5):482.e9-17.
       • Tsai MH, Wang SH, Hsu JF, Lin LC, Chu SM, Huang HR, Chiang MC, Fu RH, Lu JJ, Huang YC. Clinical and molecular characteristics of bloodstream infections caused by Candida albicans in children from 2003 to 2011. Clin Microbiol Infect. 2015 Nov;21(11):1018.e1-8.
       • Chang CC, Lee CJ, Ou LS, Wang CJ, Huang YC. Disseminated cat-scratch disease: case report and review of the literature. Paediatr Int Child Health. 2016 Jan 12:1-3. [Epub ahead of print]
       • Wan GH, Huang CG, Chung FF, Lin TY, Tsao KC, Huang YC. Detection of Common Respiratory Viruses and Mycoplasma pneumoniae in Patient-Occupied Rooms in Pediatric Wards. Medicine (Baltimore). 2016 Apr;95(14):e3014.
       • Tsai MH, Lee CW, Chu SM, Lee IT, Lien R, Huang HR, Chiang MC, Fu RH, Hsu JF, Huang YC. Infectious Complications and Morbidities After Neonatal Bloodstream Infections: An Observational Cohort Study. Medicine (Baltimore). 2016 Mar;95(11):e3078.
       • Lin TC, Mao SH, Chen CH, Chen YL, Wong HF, Chang CJ, Huang YC. Systematic Analysis of the Risk Factors Affecting the Recurrence of Traumatic Carotid-Cavernous Sinus Fistula. World Neurosurg. 2016 Jun;90:539-545.
       • Lai MY, Tsai MH, Lee CW, Chiang MC, Lien R, Fu RH, Huang HR, Chu SM, Hsu JF. Characteristics of neonates with culture-proven bloodstream infection who have low levels of C-reactive protein (≦10 mg/L). BMC Infect Dis. 2015 Aug 11;15:320.
       • Hsu JF, Chu SM, Lee CW, Yang PH, Lien R, Chiang MC, Fu RH, Huang HR, Tsai MH. Incidence, clinical characteristics and attributable mortality of persistent bloodstream infection in the neonatal intensive care unit. PLoS One. 2015 Apr 15;10(4):e0124567.
       • Hsu JF, Chu SM, Huang YC, Lien R, Huang HR, Lee CW, Chiang MC, Fu RH, Tsai MH. Predictors of clinical and microbiological treatment failure in neonatal bloodstream infections. Clin Microbiol Infect. 2015 May;21(5):482.e9-17.
       • Tsai MH, Wang SH, Hsu JF, Lin LC, Chu SM, Huang HR, Chiang MC, Fu RH, Lu JJ, Huang YC. Clinical and molecular characteristics of bloodstream infections caused by Candida albicans in children from 2003 to 2011. Clin Microbiol Infect. 2015 Nov;21(11):1018.e1-8.

2. 細菌對抗生素抗藥性之系列研究及菌血症之相關研究

邱政洵醫師、謝育嘉醫師、李浩遠醫師、吳昌騰醫師、吳竹蘭部長、蘇玲慧老師：

• Yang WC, Chan OW, Wu TL, Chen CL, Su LH, Chiu CH. Development of ceftriaxone resistance in Salmonella enterica serotype Oranienburg during therapy for bacteremia. J Microbiol Immunol Infect 2016 Feb;49(1):41-5.
• Shu JC, Su LH, Chiu CH, Kuo AJ, Liu TP, Lee MH, Su IN, Wu TL. Reduced Production of OprM May Promote oprD Mutations and Lead to Imipenem Resistance in Pseudomonas aeruginosa Carrying an oprD-Group 1A Allele. Microb Drug Resist. 2015 Apr;21(2):149-157.
• Wu CT, Chen CL, Lee HY, Chang CJ, Liu PY, Li CY, Liu MY, Liu CH. Decreased antibiotic resistance and defined daily doses after implementation of a clinical culture-guided antimicrobial stewardship program in a hospital. J Microbiol Immunol Infect. 2015; doi: 10.1016/j.jmii.2015.10.006.
• Lee HY, Huang CW, Chen CL, Wang YH, Chang CJ, Chiu CH. Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients. J Microbiol Immunol Infect. 2015 Dec;48(6):588-96.
• Yang WC, Chan OW, Wu TL, Chen CL, Su LH, Chiu CH. Development of ceftriaxone resistance in Salmonella enterica serotype Oranienburg during therapy for bacteremia. J Microbiol Immunol Infect. 2016 Feb;49(1):41-5.
• Wu CT, Lee HY, Chen CL, Tuan PL, Chiu CH. High prevalence and antimicrobial resistance of urinary tract infection isolates in febrile young children without localizing signs in Taiwan. J Microbiol Immunol Infect. 2016 Apr;49(2):243-8
• Kung YH, Hsieh YF, Weng YH, Lien RI, Luo J, Wang Y, Huang YC, Chen CL, Chen CJ. Risk factors of late-onset neonatal sepsis in Taiwan: a matched case-control study. J Microbiol Immunol Infect. 2016 Jun;49(3):430-5.

3. 細菌致病機制研究
   1. 莊智賢醫師、邱政洵醫師：綠膿桿菌之上海熱 (Shanghai fever; community-onset Pseudomonas aeruginosa enteritis and sepsis)相關致病機制: 發現並分析 hypervirulent strains of P. aeruginosa。
• Shu JC, Su LH, Chiu CH, Kuo AJ, Liu TP, Lee MH, Su IN, Wu TL. Reduced Production of OprM May Promote oprD Mutations and Lead to Imipenem Resistance in Pseudomonas aeruginosa Carrying an oprD-Group 1A Allele. Microb Drug Resist. 2015 Apr;21(2):149-157.
• Lo YL, Shen L, Chang CH, Bhuwan M, Chiu CH, Chang HY. Regulation of Motility and Phenazine Pigment Production by FliA Is Cyclic-di-GMP Dependent in Pseudomonas aeruginosa PAO1. PloS One. 2016; 11(5), e0155397.
2. 邱政洵醫師、謝育嘉醫師、蔡明翰醫師、吳昌騰醫師、魏嵩璽醫師、Rajendra-Prasad Janapatla助研究員 ：肺炎鏈球菌 (Streptococcus pneumoniae)造成溶血性尿毒症候群 (Hemolytic uremic syndrome)之細胞及分子機制。
• Wei SH, Chiang CS, Chen CL, Chiu CH. Pneumococcal disease and use of pneumococcal vaccines in Taiwan. Clin Exp Vaccine Res. 2015; 4:121-9.
• Tsai MH, Huang SH, Chen CL, Chiu CY, Hua MC, Liao SL, Yao TC, Lai SH, Yeh KW, Wang MP, Huang JL. Pathogenic Bacterial Nasopharyngeal Colonization and Its Impact on Respiratory Diseases in the First Year of Life: The PATCH Birth Cohort Study. The Pediatric infectious disease journal. 2015;34(6), 652-658.
• Hsieh YC, Lin TL, Lin CM, Wang JT. Identification of PblB mediating galactose-specific adhesion in a successful Streptococcus pneumoniae clone. Scientific reports. 2015 Jul 21; 5:12265.
• Hsieh YC, Chi H, Chang KY, Lai SH, Mu JJ, Wong KS, Liu CC, Huang YC, Lin HC, Chang LY, Huang YC, Huang LM. Increase in Fitness of Streptococcus pneumoniae is Associated with the Severity of Necrotizing Pneumonia. The Pediatric infectious disease journal. 2015; 34(5), 499-505.
• Wu CT, Lee HY,  Chen CL. A near-fatal case of invasive pneumococcal disease in a vaccinated child. Pediatr Neonatol. 2016 Feb; 57(1):76-8.
• Janapatla RP, Hsu MH, Liao WT, Chien KY, Lee HY, Chiu CH. Low Serum Fetuin-A as a Biomarker to Predict Pneumococcal Necrotizing Pneumonia and Hemolytic Uremic Syndrome in Children. Medicine. 2016; 95(13), e3221.
3. 邱政洵醫師、徐任甫醫師、王盈翔 醫師、陳奇良副研究員: B型鏈球菌(GBS)的流行病學與致病性
• Wang YH, Chen CL, Hou JN, Wang YR, Lin TY, Wang MH, Yang TH, Chu C, Chiu CH. Serotype distribution and resistance genes associated with macrolide and fluoroquinolone resistance in Streptococcus agalactiae isolates from a hospital in Southern Taiwan. Biomed J 2015; 38(3):215-220.
• Wang YH, Lu CC, Chiu CH, Wang MH, Yang TH, Chu C. Genetically diverse serotypes III and VI substitute major clonal disseminated serotypes Ib and V as prevalent serotypes of Streptococcus agalactiae from 2007 to 2012. Journal of Microbiology, Immunology and Infection. 2015 Jul 6. pii: S1684-1182(15)00778-1. doi: 10.1016/j.jmii.2015.05.022. [Epub ahead of print].
4. 微生物基因體學及蛋白質體學的研究
   1. 轉錄互動體及全基因體定序 (transcriptomic interactome and genome sequencing)
   • Feng Y, Chen CL, Chen TH, Liang YH, Chen HL, Lin CY, Chiu CH. Application of next-generation sequencing to study ascitic microbiome in cirrhotic patients with or without spontaneous bacterial peritonitis. J Microbiol Immunol Infect. 2015 Oct; 48:504-509.
   • Cheng WH, Huang KY, Huang PJ, Hsu JH, Fang YK, Chiu CH, Tang P. Nitric oxide maintains cell survival of Trichomonas vaginalis upon iron depletion. Parasit Vectors. 2015 Jul 25; 8:393.
   • Feng Y, Ruan Z, Shu J, Chen CL, Chiu CH. (2016). A glimpse into evolution and dissemination of multidrug-resistant Acinetobacter baumannii isolates in East Asia: a comparative genomics study. Scientific Reports. 2016 Apr 13; 6:24342.
5. 抗藥性金黃色葡萄球菌MRSA
   1. 邱政洵醫師、陳志榮醫師、黃玉成醫師：抗藥性金黃色葡萄球菌MRSA是全世界依學上最嚴重地問題之一，由於社區型MRSA崛起，更加重此問題的嚴重性。我們完成台灣本土社區型MRSA ST59基因體定序，並深入分析其基因序列演化的軌跡，發表重要論文，提出以dual-coding next generation sequencing (NGS)進行超通量定序(ultra deep sequencing) 可以及時準確捕捉(real-time capture)細菌突變(mutation)的軌跡。此外早在2008年，也已經以生物資訊學方法進行比較基因體學研究（Comparative genomics），探討MRSA之演化，尤其從基因體層次分析社區型MRSA的毒性機制的演化，認為與gene expression shift有關，此論文開啟後續從transcriptome層次探討社區型MRSA致病機轉的研究。
   • Lee HY, Chen CL, Liu SY, Yan YS, Chang CJ, Chiu CH. Impact of molecular epidemiology and reduced susceptibility to glycopeptides and daptomycin on outcomes of patients with methicillin-resistant Staphylococcus aureus bacteremia. PLoS One. 2015;10:e0136171.
   • Chen CJ, Huang YC, Chiu CH. Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia. Journal of Antimicrobial Chemotherapy. 2015; 70(11), 2965-2972.
   • Kung YH, Hsieh YF, Weng YH, Lien RI, Luo J, Wang Y, Huang YC, Chen CL, Chen CJ. Risk factors of late-onset neonatal sepsis in Taiwan: a matched case-control study. J Microbiol Immunol Infect. 2016 Jun;49(3):430-5.
   • Liu SH, Chen KF, Chen CJ, Lin YH, Huang YC. Intermittent nasal carriage with Staphylococcus aureus within a menstrual cycle: Results from a prospective cohort of healthy carriers. Medicine (Baltimore). 2016 Jun;95(26):e4040. 
6. 轉譯醫學研究―專利案件之申請
   1. 邱政洵醫師、陳奇良博士、黃耀廣醫師: 革蘭氏陰性菌的發光載體之開發

   我們發展革蘭陰性細菌專用之穩定自發發光載體及其製作方法，以及可多用途地導入特定基因於載體中讓活菌來表現。此系統可以直接追蹤活菌在活體動物中活動的狀況，並且適用於生物醫學和環境工程的基因改造工程，尤其可當作一多用途之載體，在基因工程的改造下，將特殊的基因導入，如免疫相關的基因產物或是毒殺腫瘤細胞的毒化物等等。

   • Chiu CH, Chen CL, and Huang YK. Method for tracing gram-negative bacteria inside animal model using stable and bioluminescence-based expression system. Patent No.: US 8,263,366 B2; Duration: May. 17, 2011~May. 17, 2030 (For method)
   • Chiu CH, Chen CL, and Huang YK. Method for tracing gram-negative bacteria inside animal model using stable and bioluminescence-based expression system. Patent No.: US 8,268,616 B2; Duration: Oct. 01, 2010~Oct. 01, 2030 (For sequence)
   • 邱政洵、陳奇良、黃耀廣：可穩定自發光的細菌質粒及其製備方法。中國大陸專利發明證號: CN102268447。有效期限: 2010年6月1日至2030年5月31日。
   • 邱政洵、陳奇良、黃耀廣；革蘭陰性細菌專用之穩定自發發光載體及其製作方法。台灣專利期限：2010/05/21~2030/05/20；台灣專利發明證號: I414599 。
   2. 邱政洵醫師、Dr. Rajendra-Prasad Janapatla、陳奇良博士等八位發明人:通用型肺炎鏈球菌蛋白疫苗之開發

   肺炎鏈球菌的感染症目前仍是主要的高死亡率和高發病率的疾病源之一，儘管目前已有多種疫苗施打來保護人們免於鏈球菌的感染，但是非疫苗的其它血清型肺炎鏈球菌卻隨之湧現出來，而且這些菌株的抗藥性和毒性也隨之增強。所以開發新的疫苗和診斷的方法，實為公眾所殷切企盼。因此我們發展使用肺炎鏈球菌神經胺酸酶作為診斷和預防肺炎鏈球菌感染症之方法。

   • Chiu CH, Janapatla RP, Chen CL, Hsu MH, Chen HL, Huang CT, Chang HJ, Liao WT; Method of detecting the presence of pneumococcal neuraminidases in Streptococcus pneumoniae–infected samples (Diagnosis); 專利發明證號：US 9,023,599 B2; Duration: 2013/2/25~ 2033/2/24.
   • Chiu CH, Janapatla RP, Chen CL, Hsu MH, Chen HL, Huang CT, Chang HJ, Liao WT; Method of diagnosing and preventing pneumococcal diseases using pneumococcal neuraminidases (Vaccine); 專利發明證號：US 9,040,057 B2; 2013/2/25~202033/2/24.
   • 邱政洵、Rajendra P. Janapatla、陳奇良、徐美華、陳秀玲、黃忠翠、張欣如、廖婉婷。使用肺炎鏈球菌神經胺酸酶作為診斷和預防肺炎鏈球菌感染症之方法。台灣專利發明證號：I482969;效期: May 1, 2015~Dec. 29, 2031. May 1, 2015~Dec. 29, 2031.
   • 邱政洵、Rajendra P. Janapatla、陳奇良、徐美華、陳秀玲、黃忠翠、張欣如、廖婉婷，具有對抗肺炎鏈球菌感染的蛋白疫苗組成物及檢測樣品中肺炎鏈球菌的方法。大陸專利申請日：2013/3/20。申請號：  201310089769.0。(大陸專利發明領證中)
   • Chiu CH, Janapatla RP, Chen CL, Hsu MH, Chen HL, Huang CT, Chang HJ, and Liao WT. Neuraminidase-based vaccine components and methods for diagnosing and preventing pneumococcal diseases. EU patent filing: 2013/4/9. Filing number: EP 13162989.1. (歐盟專利發明申請中)

    

   3. 邱政洵醫師、Dr. Rajendra-Prasad Janapatla、陳奇良博士等三位發明人: 使用血清胎球蛋白-A作為生物標誌物作為檢測小孩在肺炎鏈球菌感染時引發溶血性尿毒症及壞死性肺炎疾病的檢測方法

   在肺炎鏈球菌感染時，利用定性和定量分析血清胎球蛋白-A和其它唾液酸醣蛋白的結果，可將侵襲性肺炎鏈球菌感染的疾病（invasive pneumococcal diseases，簡稱IPD），包括壞死性肺炎和溶血性尿毒症綜合症 (hemolytic uremic syndrome，簡稱HUS)等症狀，作為與其它肺炎感染症，如大葉性肺炎患者和健康組對照之區別。依據兒童血清胎球蛋白-A的濃度水平，作為評估是否因肺炎鏈球菌感染而引發的嚴重侵襲性肺炎鏈球菌疾病之一種檢測方法。利用酶聯免疫吸附測定(enzyme linked immunosorbent assay，簡稱ELISA)和西方墨點雜交法，來檢測和評估胎球蛋白-A濃度水平，進而對兒童肺炎鏈球菌感染的嚴重程度進行分類，也可反映出兒童從溶血性尿毒綜合症病人對治療的反應及其恢復的情況。

   • 邱政洵、Rajendra P. Janapatla、陳奇良。專利發明證號：I536017;"使用血清胎球蛋白A作為生物標誌物作為檢測小孩在肺炎鏈球菌感染時引發溶血性尿毒症及壞死性肺炎疾病的檢測方法"。台灣專利效期:  2014/09/16~2034/09/15。
   • Chiu CH, Janapatla RP, Chen CL. "A method for detection of hemolytic uremicsyndrome and necrotizing pneumonia in children with pneumococcal disease using serum fetuin-A levels as a biomarker". Patent No.: US 9,261,504 B1. US patent duration: 2014/09/26~2034/09/25.